title: PI3K/Akt pathway mediates Nrf2/ARE activation in human L02 hepatocytes exposed to low-concentration HBCDs.
abstract: We investigated the effects of hexabromocyclododecanes (HBCDs) at environmentally relevant concentrations on human L02 hepatocytes and explored possible underlying molecular mechanism(s), focusing on functional interactions between the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and nuclear factor-erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathways. The results showed that low concentrations of HBCDs could stimulate cell proliferation in a "DNA-dependent protein kinase catalytic subunit" (DNA-PKcs)-dependent manner, increase protein levels and nuclear translocation of transcription factor Nrf2, and upregulate expression of its target gene heme oxygenase-1 (HO-1). Electrophoretic mobility-shift assays (EMSAs) showed that ARE was a prominent element for HO-1 induction after low-concentration HBCDs exposure. The relationship between PI3K/Akt pathway and Nrf2/HO-1 axis was demonstrated by the finding that pretreatment with PI3K inhibitors (wortmannin, LY294002) attenuated the upregulation of Nrf2 expression induced by HBCDs exposure. Furthermore, knock-down of DNA-PKcs through small interfering RNA blocked Nrf2/HO-1 axis activation in L02 cells exposed to low-concentration HBCDs. Moreover, DNA-PKcs and phosphorylated Akt at Ser(473) proved to be crucial in regulating the Nrf2-ARE pathway. Thus, the PI3K/Akt pathway is essential in regulating Nrf2-ARE pathway activation in L02 cells induced by low-concentration HBCDs.
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University , Shanghai 200444, P. R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zou
authors.forename: Cen
authors.initials: C
authors.lastname: Chen
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yu
authors.forename: Jiamo
authors.initials: J
authors.lastname: Fu
mesh_terms: D061745:Antioxidant Response Elements / Q000235:genetics*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D006842:Hydrocarbons, Brominated; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; C089796:hexabromocyclododecane; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D051057:Proto-Oncogene Proteins c-akt